In the field of medicine there has been a growing recognition of the benefits of using biocompatible crosslinked polymers for the treatment of local diseases. Local diseases are diseases that are manifested at local sites within the living animal or human body, for example atherosclerosis, postoperative adhesions, rheumatoid arthritis, cancer, and diabetes. Biocompatible crosslinked polymers may be used in drug and surgical treatments of such diseases.
Historically, many local diseases have been treated by systemic administration of drugs. In this approach, in order to achieve therapeutic levels of drugs at local disease sites, drugs are delivered (via oral administration or injection) at a high systemic concentration, often with adverse side effects. As an alternative, biocompatible crosslinked polymers may be used as carriers to deliver drugs to local sites within the body, thereby reducing the need for the systemic administration of high concentrations of drugs, while enhancing effectiveness.
Local diseases also have been treated with surgery. Many of these surgical procedures employ devices within the body. These devices may often be formed from or coated with biocompatible crosslinked polymers. For example, a surgical sealant is a device formed from biocompatible crosslinked polymers that may be used to reduce migration of fluid from or into a tissue. For surgical sealants, as with many other surgical procedures, it is sometimes necessary to leave devices in the body after surgery to provide a continuing therapeutic benefit. In such cases, it may be desired that the implant biodegrade over time, eliminating the need for a second surgical procedure to remove the implant after its usefulness has ended. Regardless of whether the implant biodegrades over time, it may also be used, as described above, to deliver drugs to local sites within the body.
Many surgical procedures are now performed in a minimally invasive fashion that reduces morbidity associated with the procedure. Minimally invasive surgery (“MIS”) encompasses laparoscopic, thoracoscopic, arthroscopic, intraluminal endoscopic, endovascular, interventional radiological, catheter-based cardiac (such as balloon angioplasty), and like techniques. These procedures allow mechanical access to the interior of the body with the least possible perturbation of the patient's body. Biocompatible crosslinked polymers may be advantageously used to form or coat many of these MIS tools. These polymers may also be used to form sutures, surgical clips, staples, sealants, tissue coatings, implants and drug delivery systems.
Most of the polymers used with MIS applications are pre-formed to a specific shape before being used in a given application. However, such pre-formed objects have limitations in MIS procedures because they, like other large objects, are difficult to transport through the small access sites afforded by MIS techniques. In addition, the shape of the pre-formed object may not be appropriate because the target tissues where such objects are likely to be used have a variety of shapes and sizes. To overcome these limitations, in situ curable or gelable biocompatible crosslinked polymer systems have been explored. The precursors of such systems are usually liquid in nature. These liquids are then transported to the target tissue and applied on the target organ or tissue. The liquid flows and conforms to the shape of the target organ. The shape of the conformed liquid is then preserved by polymerization or a gelation reaction. This approach has several advantages, including conformity to organ shapes and the ability to implant large quantities of liquid using MIS procedures.
One use of in situ curable biocompatible crosslinked polymers in MIS procedures is to form tissue coatings so as to prevent post-surgical adhesions. For example, J. L. Hill-West et al., “Prevention of Postoperative Adhesions in the Rat by In Situ Photopolymerization of Bioresorbable Hydrogel Barriers,” Obstetrics and Gynecology, 83(1):59 (1994) describes the use of free radical photopolymerizable water-soluble monomers to form biocompatible crosslinked polymers and thereby prevent post-operative adhesions in two animal models. U.S. Pat. No. 5,410,016 to Hubbell et al. describes the use of free radical photopolymerizable monomers to form biocompatible crosslinked polymers, which then are used as tissue adhesives, controlled-release carriers and as tissue coatings for the prevention of post-operative adhesions.
Free Radical Polymerization
Many of the biocompatible crosslinked polymers previously known used free radical polymerization of vinylic or acrylic functionalities. For example, the Hill-West article describes the use of free radical photopolymerizable, water soluble monomers consisting of 8000 molecular weight (“MW”) polyethylene glycol (“PEG”) extended at both ends with oligomers of lactic acid and further acrylated at both ends. The aforementioned Hubbell patent describes the use of acetophenone derivative or eosin initiated free radical polymerization of acrylic functionalities of water-soluble biodegradable macromolecules. U.S. Pat. No. 4,938,763 to Dunn describes the use of benzoyl peroxide initiated free radical polymerization of liquid prepolymers.
While free radical polymerization is useful for polymer synthesis, several considerations limit its suitability for use in the living animal or human body. First, the initiator which generates free radicals normally produces several small molecules with known or unknown toxicity. For example, one of the most commonly used photoinitiators, 2,2-dimethoxy 2-phenylacetophenone, generates methyl benzoate and other small compounds during the initiation step. The safety of these initiator fragments must be established before there can be widespread use of such systems for human or animal use. Second, free radicals are extremely reactive species and have life times ranging from 0.01 to 1 second during a typical free radical polymerization reaction. Third, the free radical polymerization, once initiated, is often uncontrollable, frequently producing polymers with high molecular weight and broad molecular weight distribution. Fourth, the most common functionalities used in free radical polymerization are vinylic or acrylic, and the vinyl/acrylic polymers produced by these compositions do not degrade inside the body. Fifth, free radical polymerizable monomers often need to be inhibited with a small amount of inhibitor to prevent the premature polymerization of vinyl functionality. The most commonly used inhibitors are phenols (for example, hydroquinone), which are toxic and hence can be used in only limited amounts, increasing the probability of premature polymerization and crosslinking. Finally, free radical polymerization is often exothermic, and the heat it generates may cause localized burn injuries.
Electrophilic-Nucleophilic Polymerization
Other crosslinked polymers have been formed using electrophilic-nucleophilic polymerization of polymers equipped with either electrophilic or nucleophilic functional groups. For example, U.S. Pat. Nos. 5,296,518 and 5,104,909 to Grasel et al. describe the formation of crosslinked polymers from ethylene oxide rich prepolymers, wherein a polyisocyanate or low molecular weight diisocyanate is used as the electrophilic polymer or crosslinker, and a polyoxyethylene based polyol with in situ generated amine groups is used as the nucleophilic precursor. U.S. Pat. No. 5,514,379 to Weissleder et al. describes the formation of biocompatible crosslinked polymers using polymeric precursors, including polyethylene glycol derivatives, each having multiple electrophilic or nucleophilic functional groups. U.S. Pat. No. 5,426,148 to Tucker describes sealant compositions based on an electrophilic-nucleophilic polymerization reaction between polyether acetoacetylate and polyether amine precursors. U.S. Pat. Nos. 5,874,500 and 5,527,856 to Rhee et al. also describe biocompatible crosslinked polymers, formed from electrophilic-nucleophilic polymerization of polymers having multiple electrophilic or nucleophilic functionalities.
While these electrophilic-nucleophilic polymerization methods do not suffer from the same limitations as free radical polymerization methods, described above, they have other limitations stemming from their use of polymeric precursors. Mixing can be a significant impediment to such reactions since polymeric precursors are often of a higher viscosity and diffusion is impeded, especially with the onset of gelation. Thus, imperfections in the crosslinked structures and weaknesses may result.
In contrast, the use of at least one small molecule precursor (where small molecule refers to a molecule that is not a polymer and is typically of a molecular weight less than 2000 Daltons, or else is a polymer and is of a molecular weight of less than 1000 Daltons) allows for diffusion of the small molecule throughout the crosslinked structure, even after gelation, and thus may result in superior materials. This approach has heretofore been limited to small molecules having electrophilic end groups such as aldehyde. For example, BioGlue, marketed by Cryolife Inc., uses a glutaraldehyde-based electrophilic small molecule to react with a polymeric albumin-based nucleophilic polymer.
However, the small molecule electrophile approaches that are known suffer from several limitations. For example, glutaraldehyde is known to be a toxic compound, and in fact is used to sterilize tissues and can cause significant tissue toxicity. For isocyanate-based approaches, in order for in situ polymerization to occur without local tissue toxicity, other crosslinkers are needed. Moreover, the prior art is silent on the subject of biodegradability of these networks. This is important because in many applications it is important that the materials absorb and be cleared from the body after having served their purpose.
Visualization
As described above, advances in modern surgery provide access to the deepest internal organs with minimally invasive surgical devices. As also described above, biocompatible crosslinked polymers that can be formed in situ are useful in such surgical procedures. However, most such formulations, for example, fibrin glue, are colorless, and the amount of material used is typically very small, leading to a film thickness of only about 0.05 to 1 mm. The resulting colorless solution or film is therefore difficult to visualize, especially in the typically wet and moist surgical environment. Under laparoscopic conditions, visibility is even more difficult due to the fact that only a two-dimensional view of the surgical field is available on the monitor that is used in such procedures.
The use of color in biocompatible crosslinked polymers and precursors may therefore greatly improve their utility in a surgical environment, especially under minimally invasive surgical procedures. Moreover, the better visibility available with the use of color also permits efficient use of materials with minimum wastage.
There thus exists a need for biocompatible crosslinked polymers that can be formed without using free radical chemistry, that can be formed from at least one small molecule precursor that has minimal tissue toxicity, that may be biodegradable, and that may be colored.